There are five broad objectives to these projects: 1) to demonstrate the specificity of the finding that the urine of patients with subacute necrotizing encephalomyelopathy (SNE, Leigh's disease) inhibits the enzyme which synthesizes thiamine triphosphate (TTP) thus leading to low proportions of TTP in the brain; 2) to seek a chemical model for SNE by the use of certain antimetabolites (pyrithiamine, plasmocid); 3) to determine whether disruption of the interchange between thiamine pyrophosphate (TPP) and TTP is the basi neurochemical deficit in both dietary thiamine deficiency and SNE; 4) to determine what is the most efficacious therapy for both conditions with respect to thiamine and its derivative thiamine tetrafurfuryldisulfide (TTFD); and 5) to determine the role of thiamine in membrane function.